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Tumor Microenvironment Regulation by the Endoplasmic Reticulum Stress Transmission Mediator Golgi Protein 73 in Mice
Author(s) -
Wei Congwen,
Yang Xiaoli,
Liu Ning,
Geng Jin,
Tai Yanhong,
Sun Zhenyu,
Mei Gangwu,
Zhou Pengyu,
Peng Yumeng,
Wang Chenbin,
Zhang Xiaoli,
Zhang Pingping,
Geng Yunqi,
Wang Yujie,
Zhang Xiaotong,
Liu Xin,
Zhang Yanhong,
Wu Feixiang,
He Xiang,
Zhong Hui
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30549
Subject(s) - unfolded protein response , endoplasmic reticulum , proinflammatory cytokine , golgi apparatus , microbiology and biotechnology , secretion , tumor microenvironment , biology , inflammation , cancer research , signal transduction , chemokine , immunology , endocrinology , tumor cells
The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor‐promoting inflammation by up‐regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi‐associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor‐associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose‐regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion : Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.